Negative selection of patients (pts) with HER2-positive and <i>RAS</i> wild-type (wt) metastatic colorectal cancer (mCRC) receiving dual HER2 blockade.
Authors: Giovanni Randon, Yoshiaki Nakamura, Rona Yaeger, Sara Lonardi, Chiara Cremolini, Elena Elez, Federico Nichetti, Filippo Ghelardi, Vincenzo Nasca, Francesca Bergamo, Veronica Conca, Javier Ros Montañá, Giulia Maddalena, Michele Prisciandaro, Hideaki Bando, Alexa Betzig Schrock, Henry S. Walch, Takayuki Yoshino, Filippo Pietrantonio
Journal: Journal of Clinical Oncology (2023)

e15164 Background: Refining the selection of pts with HER2-positive mCRC for dual HER2 blockade is a challenge for precision oncology. Alterations in receptor tyrosin-kinase (RTK)/MAPK pathway and HER2 gene copy number (GCN) are promising predictive biomarkers for primary resistance or sensitivity, respectively. Methods: We conducted a multicentric case-control study to evaluate the negative predictive impact of a panel of candidate genomic alterations of primary resistance (PRESSING-HER panel) in pts with HER2-positive, RAS wt mCRC treated with trastuzumab-based dual HER2 blockade. Comprehensive genomic profiling was performed on archival pre-treatment tumor samples and screening sources were: the TRIUMPH trial (Oncomine Comprehensive Assay), the Italian-Spanish observational cohort (Foundation One CDx) and the MSKCC cohort (MSK-IMPACT). The panel grouped resistance alterations with a solid biological rationale as on-target, i.e. HER2 pathogenic mutations or rearrangements or off-target, i.e. mutations/amplifications in RTK/MAPK genes. Primary resistance was defined by PFS &lt; 4 months (mos), sensitivity was defined by PFS ≥4 mos. Hypothesizing a prevalence of PRESSING-HER alterations equal to 5% and 30% among controls and cases, respectively, 35 cases and 35 controls were needed to reject the null hypothesis of equally prevalent alterations, with α and β errors of 0.05 and 0.20. HER2 GCN was derived from NGS and the cut-off was calculated by ROC curve analyses using 4-month PFS rate as endpoint. Results: Sixty-eight pts were evaluable (33 resistant and 35 sensitive). In the overall population, PRESSING-HER alterations were found in 14 (20.6%) pts and included HER2 mutations in 7 (50%), HER2 rearrangements in 4 (29%), BRAF class 1 mutations in 2 (14%) and EGFR amplification in 1 (7%). PRESSING-HER alterations were significantly more frequent in pts with primary resistant (12/21, 57%) versus (vs) sensitive tumors (2/35, 6%; P= 0.004). HER2 GCN had a median value of 34.5 (IQR: 18.7-78.5) and an optimal cut-off of 33. In multivariable analyses including the main baseline clinical prognostic features, PRESSING-HER alterations were independently associated with inferior PFS (median PFS 2.0 vs 5.4 mos; adjusted HR 3.5, 95%CI 1.7-7.0; P&lt; 0.001) and OS (median OS 3.7 vs 14.8 mos; adjusted HR 3.9, 95%CI 1.8-8.3; P&lt; 0.001). HER2 GCN &lt; 33 was associated with significantly inferior median PFS (2.6 vs 5.4 mos; adjusted HR 1.8, 95%CI 1.0-3.1; P= 0.038) and numerically inferior OS (median OS 9.1 vs 15.4 mos; adjusted HR 1.3, 95%CI 0.7-2.5; P= 0.356). The predictive accuracy of PRESSING-HER was 66% and it was increased to 77% when combined with HER2 GCN. Conclusions: The combined assessment of HER2 on/off-target alterations and HER2 GCN stratifies patient outcomes to HER2 dual blockade.